Initial Liver Stiffness Research Articles

Deep learning for predicting fibrotic progression risk in diabetic individuals with metabolic dysfunction-associated steatotic liver disease initially free of hepatic fibrosis

ObjectiveMetabolic dysfunction-associated steatotic liver disease (MASLD) significantly impacts patients with type 2 diabetes mellitus (T2DM), where current non-invasive assessment methods show limited predictive power for future fibrotic progression. This study aims to develop an enhanced deep learning (DL) model that integrates ultrasound elastography images with clinical data, refining the prediction of fibrotic progression in T2DM patients with MASLD who initially exhibit no signs of hepatic fibrosis. MethodsWe enrolled 946 diabetic MASLD patients without advanced fibrosis, confirmed by initial liver stiffness measurements (LSM) below 6.5 kPa. Patients were divided into a training dataset of 671 and a testing dataset of 275. Hepatic shear wave elastography (SWE) images measured liver stiffness, classifying participants based on progression. A DL integrated model (DI-model) combining SWE images and clinical data was trained and its predictive performance compared with individual Image and Tabular models, as well as a logistic regression model on the testing dataset. ResultsFibrotic progression was observed in 18.1 % of patients over three years. During the training phase, the DI-model outperformed other models, achieving the lowest validation loss of 0.161 and highest accuracy of 0.933 through cross-validation. In the testing phase, it demonstrated robust discrimination with AUCs of 0.884 and 0.903 for the receiver operating characteristic and precision-recall curves, respectively, clearly outperforming other models. Shapley analysis identified BMI, LSM, and glycated hemoglobin as critical predictors. ConclusionThe DI-model significantly enhances the prediction of future fibrotic progression in diabetic MASLD patients, demonstrating the benefit of combining clinical and imaging data for early diagnosis and intervention.

Associations of Liver Stiffness Measured by Ultrasound Shear-Wave Elastography With Portal Hypertension and Circulatory Failure in Individuals With Fontan Circulation.

BACKGROUND. The Fontan operation palliates single-ventricle congenital heart disease but causes hepatic congestion with associated progressive hepatic fibrosis. OBJECTIVE. The purpose of this study was to evaluate associations between liver stiffness measured using ultrasound (US) shear-wave elastography (SWE) in patients with Fontan palliation and the occurrence of portal hypertension and Fontan circulatory failure during follow-up. METHODS. This retrospective study included 119 individuals 10 years old or older (median age, 19.1 years; 61 female patients, 58 male patients) with Fontan circulation who underwent liver US with 2D SWE from January 1, 2015, to January 1, 2022, and had 1 year or more of clinical follow-up (unless experiencing earlier outcome-related events). Median liver stiffness from the initial US examination was documented. Varices, ascites, splenomegaly, and thrombocytopenia (VAST) scores (range, 0-4) were determined as a marker of portal hypertension on initial US examination and 1 year or more of follow-up imaging (US, CT, or MRI). Composite clinical outcome for Fontan circulatory failure (death, mechanical circulatory support, cardiac transplant, or unexpected Fontan circulation-related hospitalization) was assessed. Analysis included the Wilcoxon rank sum test, logistic regression analysis with stepwise variable selection, and ROC analysis. RESULTS. Median initial liver stiffness was 2.22 m/s. Median initial VAST score was 0 (IQR, 0-1); median follow-up VAST score was 1 (IQR, 0-2) (p = .004). Fontan circulatory failure occurred in 37 of 119 (31%) patients (median follow-up, 3.4 years). Initial liver stiffness was higher in patients with a follow-up VAST score of 1 or greater (2.37 m/s) than in those with a follow-up VAST score of 0 (2.08 m/s) (p = .005), and initial liver stiffness was higher in patients with (2.43 m/s) than without (2.10 m/s) Fontan circulatory failure during follow-up (p < .001). Initial liver stiffness was the only significant independent predictor of Fontan circulatory failure (OR = 3.76; p < .001); age, sex, Fontan operation type, dominant ventricular morphology, and initial VAST score were not independent predictors. Initial liver stiffness had an AUC of 0.70 (sensitivity, 79%; specificity, 57%; threshold, > 2.11 m/s) for predicting a follow-up VAST score of 1 or greater and an AUC of 0.74 (sensitivity, 84%; specificity, 52%; threshold, > 2.12 m/s) for predicting Fontan circulatory failure. CONCLUSION. In patients with Fontan circulation, increased initial liver stiffness was associated with portal hypertension and circulatory failure during follow-up, although it had moderate performance in predicting these outcomes. CLINICAL IMPACT. US SWE may play a role in post-Fontan surveillance, supporting tailored medical and surgical care.

Transient Elastography Accurately Screens for Compensated Advanced Chronic Liver Disease in Patients With Ongoing or Recent Alcohol Withdrawal

Liver stiffness measurement by transient elastography (TE) is a promising method for staging fibrosis in alcohol-related liver disease, but uncertainties remain regarding the influence of alcohol consumption and thus the ideal timing for TE performance. We evaluated the performance of TE compared with liver biopsy to exclude compensated advanced chronic liver disease (cACLD) in patients hospitalized for alcohol detoxification. Patients were recruited prospectively at 6 in-patient addiction centers in France. Eligible patients had increased aspartate aminotransferase levels, and no history or signs of overt cirrhosis. TE, histology, and biochemistry measurements were obtained within a median of 6 days after alcohol withdrawal. TE and biochemistry were repeated 1 and 2 months later. The study included 259 patients for per-protocol analysis, of whom 45 (17%) had cACLD. TE identified patients with high accuracy at inclusion and at the 1- and 2-month follow-up evaluation, with area under the curve values of 0.96 (95% CIs, 0.94-0.99), 0.96 (95% CIs, 0.92-0.99), and 0.93 (95% CIs, 0.85-1.00), respectively. In 84% of patients, cACLD was ruled outwhen liver stiffness was less than 10 kPa (negative predictive value, 99% (95% CIs, 98%-100%)) or ruled in when greater than 25 kPa (positive predictive value, 93% (95% CI, 83%-102%)). Algorithms based on aminotransferase levels and/or bilirubin did not add to the diagnostic performance of TE in this period. Among patients with initial liver stiffness of 10 to 25 kPa, more than half of those with no cACLD showed liver stiffness of less than 10 at 1- and 2-month follow-up testing. TE performed during the first 2 months after alcohol cessation is an excellent method for excluding alcohol-related cACLD. NCT01789008.

Liver elastometry and alcohol withdrawal: Median-term follow-up in a psychiatric unit.

The measurement of liver stiffness (LS) shows promise as a follow-up tool after alcohol withdrawal, but it has mainly been studied in the early phase or in patients with severe liver disease. A 6-month ancillary study of a specific psychiatric cohort of alcoholic patients without known liver disease followed after withdrawal was conducted (Clinical Trial NCT01491347). Clinical and biological data and LS values were collected every 2 months. A total of 129 patients were included in the study; 93 had an LS assessment within the first 7 days, and 37 had all four LS measurements. Only seven (7.5%) patients had an initial LS>12.1kPa, the threshold used to define severe fibrosis. Abstinence was not associated with changes in LS at the various median-term follow-up periods. However, LS of abstinent subjects decreased significantly relative to that of non-abstinent subjects between M0 and M2. CAP™ values were not associated with abstinence. The systematic median-term follow-up of withdrawn patients does not appear to be contributory. However, LS could help to detect relapse in the first 2 months after withdrawal for subjects treated in a psychiatric hospital for dependence. It thus could serve as a motivation tool. Prospective studies with various and higher baseline LS values are warranted for simultaneous longitudinal assessment, including for very short- and long-term LS after withdrawal.

Clinical outcomes and management of patients with chronic hepatitis B and liver stiffness measurement in the grey zone.

A significant number of patients have liver stiffness measurements in the grey zone where liver biopsy is recommended. To study chronic hepatitis B patients with initial liver stiffness measurements in the grey zone with regards to rates of liver biopsy, repeat liver stiffness measurements and outcomes. Consecutive chronic hepatitis B patients who underwent transient elastography from August 2006 to July 2017 were retrospectively studied. Liver-related events were defined as hepatocellular carcinoma or cirrhotic complications. Grey zone was defined as liver stiffness measurements: 6.1-9.0kPa (normal ALT) or 7.6-12.0kPa (ALT 1-5×upper limit of normal) on M-probe and 6.9-10.0kPa on XL-probe. Of the 3212 patients analysed, 837 (26%) had initial liver stiffness measurements in grey zone. Only 3.6% of grey zone patients proceeded to liver biopsy within 6months of transient elastography, of which 33% had METAVIR F3-4 fibrosis. Repeat liver stiffness measurements was performed in 44% of grey zone patients. Liver biopsy and repeat liver stiffness measurements prompted change in management in 47% and 31% of patients respectively. Independent predictors for liver-related events in grey zone patients included increased age, low albumin and low platelet count. Liver-related events rates were increased (9%-17%) in patients with METAVIR>F2 fibrosis on biopsy or repeat liver stiffness measurements which did not improve. Chronic hepatitis B patients with initial liver stiffness measurements in the grey zone rarely proceed to a clarifying liver biopsy which would reveal advanced fibrosis or cirrhosis in one-third of patients. Both liver biopsy and repeat liver stiffness measurements in grey zone patients have clinical utility in prompting changes in management and providing prognostic information.

Assessment of Liver Disease Progression in Cystic Fibrosis Using Transient Elastography.

Cystic fibrosis-related liver disease (CFLD) can develop silently in early life and approximately 10% of children with cystic fibrosis (CF) become cirrhotic before adulthood. Clinical, biological, and ultrasound criteria used to define CFLD often reveal liver involvement at an advanced stage. The aim of this retrospective study was to assess the progression of liver stiffness measurement (LSM) in pediatric patients with CF. The change of LSM, expressed as kPa/year and %/year, was measured using transient elastography (Fibroscan) in 82 children with CF (median age: 6.8 years, interquartile range [IQR]: 5.8). Mean time interval between the 2 LSM was 3.5 years. Median initial liver stiffness was 3.7 kPa (IQR: 1.3), and then progressed by 0.23 kPa/year, that is, 6%/year. The 7 patients who developed CFLD had a higher initial level of alanine aminotransferase (50 [IQR: 15] vs 30 [IQR: 18], P = 0.0001) and presented a more rapid progression of LSM (0.94 vs 0.23 kPa/year, P = 0.02). The present study shows that the slope of worsening of liver stiffness is greater in patients who will develop CFLD, suggesting that annual transient elastography may be useful to detect risk of severe liver disease at an earlier stage.

Assessment of pathologic increase in liver stiffness enables earlier diagnosis of CFLD: Results from a prospective longitudinal cohort study.

About 30% of patients with Cystic Fibrosis (CF) develop CF-associated liver disease (CFLD). Recent studies have shown that transient elastography (TE), as a method to quantify liver stiffness, allows non-invasive diagnosis of CFLD in adults and children with CF. Within this study we aimed to prospectively identify patients at risk for development of CFLD by longitudinal analysis of liver stiffness and fibrosis scores in a 5-year follow-up. 36 pediatric and 16 adult patients with initial liver stiffness below the cut-off value indicative of CFLD (6.3 kPa) were examined by transient elastography for 4–5 years. TE, APRI-, and FIB-4-scores were assessed and compared by Kruskal-Wallis test and receiver operating characteristic (ROC)-analysis. Frequencies were compared by Chi2-test. Among the 36 patients participating in this study, a subgroup of 9 patients developed liver stiffness >6.3 kPa after 4–5 years with an increase of ΔTE >0.38 kPa/a (the group with increasing liver stiffness was labelled TEinc). APRI- and FIB-4 scores confirmed the rationale for grouping. The frequency of CFLD assessed by conventional diagnosis was significantly higher in TEinc-group compared to the control group (TEnorm). None of the adult CF patients matched criteria for TEinc-group. For the first time it was shown that the non-invasive longitudinal assessment of TE allows identification of patients with progression of CFLD in a subgroup of juvenile but not in adult CF patients. Comparing TE to conventional fibrosis-scores underlined the strength of the continuous assessment of liver stiffness for the exact diagnosis of progressive CFLD. The newly described cut-off for pathologic increase of liver stiffness, ΔTEcutoff = 0.38kPa/a, might enable to detect developing CFLD using consequent follow up TE measurements before reaching the level of stiffness indicating established CFLD. Nevertheless, the limited size of the analyzed cohort should encourage a prospective, multi-center, long term follow up study to confirm the suggested cut-off for the rise in liver stiffness.

Chronic hepatitis B patients with high liver fibrosis levels should receive antiviral treatment.

The present study aimed to evaluate improvements in liver stiffness (LS) measured by transient elastography (TE) and associated factors in Chinese patients with chronic hepatitis B (CHB) treated with entecavir (ETV). A total of 190 consecutive CHB patients who received entecavir therapy and two LS measurements (LSMs) were enrolled in this retrospective study (average age, 47 years; 137 males [72.1%]), including 111 patients without liver cirrhosis (group 0) and 79 patients with liver cirrhosis (group 1). Each patient received LSM twice with an interval of six months. Normalized aspartate aminotransferase (AST) levels were accompanied by a significant reduction in LSM values (P<0.001) in each group. Multivariate analysis revealed that a higher initial LS value in groups 0 and 1, and a higher prothrombin time activity in group 1 was associated with a greater decline of the LS value. Higher initial quantitative hepatitis B surface antigen (qHBsAg) levels were correlated with a greater decline of the qHBsAg value in the two groups. In conclusion, LS values in CHB patients significantly improved after 24 weeks of entecavir therapy. The results suggested that higher LSM values at baseline contributed to a greater regression of LSM, and higher initial qHBsAg values could lead to greater qHBsAg reduction during ETV therapy. Extrapolating our results, we might be able to consider CHB patients who have higher initial LSM values or have higher levels of qHBsAg values when enrolled would have more benefit during ETV treatment.

Changes in liver stiffness and its associated factors during oral antiviral therapy in Chinese patients with chronic hepatitis B.

The present study aimed to assess improvements in liver stiffness determined by transient elastography and associated factors in Chinese patients with chronic hepatitis B (CHB) during long-term treatment with oral antiviral drugs. A total of 334 consecutive Chinese patients with CHB who underwent oral antiviral therapy and received at least two liver stiffness measurements (LSMs) at the First Hospital of Jilin University (Changchun, China) from December 2012 to February 2015 were enrolled in the present study. The cohort included 201 patients without liver cirrhosis (group 0) and 133 patients with liver cirrhosis (group 1). Each patient was subjected to LSM twice with an interval of 6 months. The mean initial liver stiffness values were 14.01±9.37 and 21.59±10.25 kPa for patients in group 0 and group 1, respectively (P<0.001). Multivariate analysis revealed that higher aspartate aminotransferase and lower alanine aminotransferase levels at baseline as well as higher α-fetoprotein levels at follow-up (24 weeks) were associated with a greater decline of liver stiffness in group 0. Furthermore, a higher liver stiffness at baseline and a longer course of antiviral therapy prior to the initial LSM were significantly correlated with a reduction of liver stiffness, whereas higher total bilirubin levels at follow-up contributed to increased liver stiffness in group 1. In conclusion, LSM at the beginning and the end of a 24-week observation period showed that antiviral drug therapy significantly improved in group 1, while a marked decreasing trend was also observed in group 0. In group 0, the reduction of liver stiffness was correlated with liver inflammation, whereas in group 1, it was correlated with the treatment duration prior to the initial LSM and serum levels of hepatitis B virus DNA. Furthermore, a higher liver stiffness at baseline was associated with a greater reduction of liver stiffness in each group.

The Changes of Liver Stiffness and Its Associated Factors for Chronic Hepatitis B Patients with Entecavir Therapy

Liver stiffness measurement (LSM) using transient elastography has been proposed to assess liver fibrosis well in various liver diseases. This study was to determine the changes of LSM and its associated factors for chronic hepatitis B (CHB) patients undergoing Entecavir therapy. Consecutive CHB patients underwent Entecavir therapy with two LSMs were enrolled. Patients with aspartate transaminase (AST) and/or alanine transaminase ≧200 IU/L were excluded. The retrospective study enrolled 233 patients including 132 without cirrhosis (group 1) and 101 with cirrhosis (group 2). The mean values of initial liver stiffness were 7.9 and 16.6 kPa for patients in group 1 and group 2, respectively (p<0.001). In addition to the decline of transaminase levels, there was significant reduction of liver stiffness value in a mean interval of 52.8 and 61.9 weeks between the two LSMs for patients in group 1 and 2, respectively (p<0.001). Multivariate analysis showed that higher initial LSM value and presence of hepatitis B e-antigen were associated with a greater decline of LSM value, whereas follow-up AST≧40 IU/L with increased LSM value for group 1 patients. For group 2 patients, longer interval between the two LSMs, higher initial LSM value and AST≧40 IU/L were associated with a greater decline of LSM value, whereas presence of diabetes mellitus (DM) contributed to increased LSM value. In conclusion, CHB patients improved their LSM values after Entecavir therapy. Higher initial LSM value contributed to greater LSM reduction. However, in cirrhotic patients, DM was associated with an increased LSM value after therapy.

Antiretroviral Therapy and Sustained Virological Response to HCV Therapy are Associated with Slower Liver Fibrosis Progression in HIV–HCV-Coinfected Patients: Study from the Anrs Co 13 Hepavih Cohort

The aim of this study was to describe changes in repeated liver stiffness (LS) measurements and to assess the determinants of increase in LS in HIV-HCV-coinfected patients. HIV-HCV-coinfected adults enrolled in the ANRS CO 13 HEPAVIH cohort, for whom two results of LS, evaluated over ≥24 months, were available. Patients with unreliable LS results were not included. LS was measured at baseline and every year thereafter. Determinants of LS increase were assessed using linear (primary outcome: last LS minus first LS value) and logistic (secondary outcome: ≥30% increase in the initial LS value) regression analyses. A total of 313 patients (mean age 45 years, 67.4% male) were included. Overall, 93.9% were receiving antiretroviral treatment (ART). The mean baseline CD4(+) T-cell count was 471 cells/mm(3) and 72.2% of patients had undetectable plasma HIV RNA. The mean interval between the first and last LS measurements was 33.5 months. No significant difference was found between baseline and follow-up mean LS values (P=0.39). However, a decrease of ≥30% in LS was observed in 48 (15.3%) patients and an increase of ≥30% in 64 (20.5%) patients. In multivariate linear and logistic analyses, excessive alcohol intake (β coefficient 6.8; P=0.0006) and high HCV viral load (OR 1.7, 95% CI 1.1, 2.5; P=0.01) were independently associated with an increase in LS, whereas time on ART>114.5 months (OR 0.5, 95% CI 0.3, 0.9; P=0.03) and achievement of sustained virological response (OR 0.1, 95% CI 0.01, 0.9; P=0.04) were independently associated with no increase in LS. Our findings show that long-term ART and achieving sustained virological response in HIV-HCV-coinfected patients are both significantly associated with lack of increase in LS over a 33-month period.

Liver stiffness decrease after effective antiviral therapy in patients with chronic hepatitis C: Longitudinal study using FibroScan

The aim of the present study was to assess the changes of liver stiffness (LS) and its associated factors in patients with chronic hepatitis C virus infection (HCV) after interferon (IFN)-based therapy. Patients with chronic HCV who had previously undergone at least 20 weeks of IFN-based therapy were enrolled. The patients' initial LS measurement was taken at the time of enrollment, and a second LS measurement was made after an interval of at least 38 weeks. LS measurement was carried out with FibroScan, and changes of LS and its associated factors were analyzed. One hundred and forty-four patients, including 95 sustained virological response (SVR) patients and 49 non-sustained virological response (NSVR) patients, were enrolled. There was a significant decrease of LS among SVR patients (median, 0.6; P < 0.001). NSVR patients showed an increase of LS (median, 0.8; P = 0.557). For SVR patients, a high initial LS was the predictive factor of a rapid reduction of LS values. However, advanced fibrosis stage before therapy, higher body mass index (BMI) and longer time remission were predictive factors for slow reduction of LS values. LS decreases in sustained responders following IFN-based therapy in patients with chronic HCV. Advanced fibrosis, higher BMI, longer time for remission and lower initial LS value are predictive factors for a slow improvement of LS in sustained responders.

Liver stiffness is directly influenced by central venous pressure

Liver stiffness (LS) as measured by transient elastography [Fibroscan] offers a novel non-invasive approach to assess liver cirrhosis. Since Fibroscan seems to be unreliable in patients with congestive heart failure, it remains to be determined whether hemodynamic changes affect LS irrespective of fibrosis. Using landrace pigs, we studied the direct relationship between the central venous pressure and LS measured by Fibroscan. Clamping of the inferior caval vein increased LS from 3.1 to 27.8kPa while reopening reversed LS within 5min to almost normal values of 5.1kPa. We then studied LS as a function of venous pressure in the isolated pig liver by clamping the upper and lower caval, portal vein and hepatic artery. The stepwise increase of intravenous pressure to 36cm of water column (3.5kPa) linearly and reversibly increased LS to the upper detection limit of 75kPa. We finally measured LS in 10 patients with decompensated congestive heart failure before and after recompensation. Initial LS was elevated in all patients, in 8 of them to a degree that suggested liver cirrhosis (median 40.7kPa). Upon recompensation with a median weight loss of 3.0kg, LS decreased in all 10 patients down to a median LS of 17.8kPa. Inflammation could not account for increased LS since initial liver enzyme counts were only slightly elevated and did not change significantly. LS is a direct function of central venous pressure which should be considered when assessing the degree of fibrosis.

Food intake increases liver stiffness in patients with chronic or resolved hepatitis C virus infection

Transient elastography is increasingly being used in patients with chronic liver disease. It has proven particularly useful to identify patients with advanced fibrosis or cirrhosis, while classification of no or little fibrosis appears to be difficult. In general, stiffness values <6 kPa are considered normal, whereas patients with higher levels are candidates for a disease-specific treatment or further diagnostic evaluation. Parameters influencing liver stiffness may include food intake that increases liver blood flow. In a pilot study, transient elastography was performed in eight patients with chronic hepatitis C at fasting and serially for 180 min after intake of a standardized breakfast. Confirmatory, 56 patients and 19 controls underwent liver stiffness determination at fasting, directly after meal intake and 1 h after breakfast. Liver stiffness significantly increased immediately after food intake for up to 60 min (P=0.01) before normalizing after 180 min. An intraindividual analysis showed a significant increase in 22 out of 43 patients with an initial liver stiffness <or=10 kPa. An increase of at least 1 kPa after food intake was found in 24 out of 43 (56%) patients with initial stiffness <or=10 kPa. Notably, nine out of 23 (39%) patients with normal initial liver stiffness (<6 kPa) had a value of >6 kPa after food intake, potentially leading to unnecessary treatment or diagnostic procedures. Food intake increases liver stiffness in patients with hepatitis C virus infection and healthy controls. To standardize liver stiffness evaluation, we suggest measurement in the fasting condition.

Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage

Transient elastography [FibroScan (FS)] is a rapid, noninvasive, and reproducible method for measuring liver stiffness, which correlates with the degree of liver fibrosis in patients with chronic hepatitis. Whether FS is useful in the detection of preexisting liver fibrosis/cirrhosis in patients presenting with acute liver damage is unclear. Patients with acute liver damage of different etiologies were analyzed. Liver stiffness was measured during the acute phase of the liver damage and followed up to the end of the acute phase. A total of 20 patients were included in the study. In 15 of the 20 patients, initial liver stiffness values measured by FS during the acute phase of the liver damage were suggestive of liver cirrhosis. However, none of these 15 patients showed any signs of liver cirrhosis in the physical examination, ultrasound examination, or liver histology [performed in 11 of 15 (73%) patients]. A significant difference was observed in the initial bilirubin levels (5.8 +/- 6.5 mg/dL versus 15.7 +/- 11.8 mg/dL; P = 0.042) and age (32.4 +/- 17.5 years versus 49.7 +/- 15.8 years; P = 0.042) between patients with liver stiffness below or above 12.5 kPa. Six patients with initially high liver stiffness were followed up to abatement of the acute hepatitic phase; in all of them, liver stiffness values decreased to values below the cutoff value for liver cirrhosis. Transient elastography frequently yields pathologically high values in patients with acute liver damage and is unsuitable for detecting cirrhosis/fibrosis in these patients.